Shorter regimen an option for rifampicin-resistant TB
A shorter regimen comprising a seven-drug cocktail which included high-dose moxifloxacin for 9 months was noninferior to the WHO*-recommended long regimen of 20 months for treating rifampicin-resistant tuberculosis (TB), according to the STREAM** study, providing a feasible and lower-cost treatment option in resource-poor setting.
Multidrug-resistant TB is more difficult and costly to treat than drug-susceptible TB, and often requires drugs with considerable side effects.
“The shorter regimen has distinct advantages for the patient (eg, shorter treatment duration and greater adherence) and the TB treatment programme (eg, standardized, less expensive, and fewer patients lost to follow-up),” noted Dr Gavin Churchyard from the School of Public Health, University of Witwatersrand in Johannesburg, South Africa in an accompanying editorial. [N Engl J Med 2019;380:1279-1280]
In the phase III noninferiority trial, 383 patients (61 percent male) with rifampicin-resistant TB susceptible to aminoglycosides and fluoroquinolones were randomized 2:1 to receive a short regimen*** spanning 9–11 months or a long regimen of 20 months as recommended by the 2011 WHO guidelines. [N Engl J Med 2019;380:1201-1213]
The primary outcome of a favourable status, defined by “cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavourable outcome”, was achieved in similar proportion of patients in the long- and short-regimen groups (79.8 percent vs 78.8 percent).
The difference between groups was 1.0 percentage point after adjusting for HIV status (95 percent confidence interval [CI], -7.5 to 9.5), which met the prespecified criteria for noninferiority of ≤10 percent in the upper 95 percent CI limit (p=0.02 for noninferiority).
Noninferiority between the two regimens remained in the per-protocol analysis (adjusted difference, -0.7 percentage points, 95 percent CI, -10.5 to 9.1), whereby participants who did not adhere to protocol-specified treatment course for reasons other than treatment failure or death were excluded.
In view of the current findings and those from previous observational studies, WHO has updated its guidelines for multidrug- and rifampicin-resistant TB in 2018 to include the short regimen as an option for those “who have not been previously treated for more than 1 month with second-line medicines used in the shorter multidrug-resistant regimen or in whom resistance to fluoroquinolones and second-line injectable agents has been excluded.” [https://www.who.int/tb/publications/2018/ WHO.2018.MDR-TB.Rx.Guidelines.prefinal.text.pdf]
Better but ‘not good enough’
“Although the results of the STREAM study provide evidence for the efficacy of a shorter regimen, they by no means represent a triumph for patients or practitioners,” commented Churchyard. “The shorter regimen spares patients the burden of a year or more of taking daily medications; however, in the STREAM study, the overall percentage of patients who had severe side effects did not differ notably between the treatment groups.”
“Importantly, the shorter regimen still includes 4 months of painful injections with an aminoglycoside that include the associated risk of ototoxic and nephrotoxic effects,” he wrote. “Thus, although the shorter regimen is definitely better when it comes to treating multidrug-resistant and rifampicin-resistant TB, it is not good enough.”
There was no obvious difference in the incidence of severe adverse events (AEs; grade ≥3) between the long- and the short-regimen groups (45.4 percent vs 48.2 percent). Deaths were reported in 8.5 percent of patients treated with a short regimen compared with 6.4 percent of those who received a long regimen.
More patients in the short-regimen group had prolonged QT interval (11.0 percent vs 6.4 percent; p=0.14), which was a known side effect of clofazimine and fluoroquinolones used in the short regimen, indicating that regular ECG monitoring was essential to identify QT interval prolongation so that treatment can be modified when required.
As such, fluoroquinolones in the current study are replaced by levofloxacin in the second-stage STREAM study, which according to the researchers, will evaluate whether a short regimen administered entirely through the oral route is similarly effective and thus avoid the aminoglycoside-associated toxicities.
“Elimination of injectable agents would be a major advance for patients and programmes,” commented Churchyard. “To expand treatment access and maximize treatment outcomes, an all-oral, even shorter (≤6 months), safer, and more efficacious regimen is required.”